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LOT and HOT … or not. The proliferation of clinically insignificant and poorly characterised types of renal neoplasia

Published:October 18, 2022DOI:https://doi.org/10.1016/j.pathol.2022.09.002

      Summary

      The classification of malignant tumours is influenced by both immunohistochemical and molecular genetic findings. This is highlighted in the latest World Health Organization classification of renal neoplasia, which has a tumour category of ‘tumours that are molecularly defined’. This implies that the defining molecular features are integral to tumourigenesis, which may not necessarily be the case. Renal oncocytoma is recognised as a benign tumour with variable morphology and immunoexpression. A variant of these tumours is hybrid oncocytic chromophobe tumour, which has features of both oncocytoma and chromophobe renal cell carcinoma and may, on rare occasions, show malignant behaviour. Recent reports have proposed two further entities with eosinophilic cytoplasm and varying nuclear pleomorphism, designated low grade oncocytic tumour (LOT) and eosinophilic vacuolated tumour (EVT), formally known as high grade oncocytic tumour (HOT). The diagnosis of these apparently benign tumours was made on the basis of morphological and immunohistochemical features. More recently it has been claimed that the mutations in the mTOR pathway are also a diagnostic feature and it is further suggested that these mutations are key to the pathogenesis of these tumours. As is seen in oncocytoma, immunohistochemical expression of tumours included in series of LOT and EVT is variable. The mutations in the mTOR pathway, where detected, were not constant, with any combination of mTOR, TSC1 and/or TSC2 being involved. A major issue is that in many of the studies full comparative genomic hybridisation results are not presented. In addition it is well recognised that mTOR mutations are seen in a variety of renal tumours. In view of these conflicting results, the rarity of these tumours and their apparent benign nature, raises questions as to why these tumours should be considered specific entities.

      Key words

      Introduction

      The key role of a pathologist is to classify tumours into categories that inform both treatment and prognostic assessment. In general tumours are characterised according to morphological features and for this reason diagnostic features are well established, resulting in minimal inter-observer error. The validity of any diagnostic entity is questionable if its features are not well established or if there are significant differences in outcome that are not predictable on histological examination.
      For the classification of tumours according to histotype, practising pathologists are aware that tumours within each diagnostic category in any organ system are not identical to each other. One or more of a variety of architectural patterns and cytological features can be found in the vast majority of tumours and for this reason variant histologies have been described, not uncommonly, in tumours from many organs. Even without such variability, individual tumours can differ from each other due to inherent characteristics of both the neoplastic cells themselves and the reaction of the host tissue. Despite recognised variations in morphology, it is accepted that as long as the overall features of a tumour are those of a specific diagnostic entity, and importantly, if there is no difference in outcome, then there is no justification in establishing additional diagnostic categories based on subtle morphological differences. In urological pathology there are clear examples of lesions that fulfil these criteria.
      Adenomatoid tumour of the genitourinary tract can have a variety of morphological patterns, but rather than labelling each variant as a different tumour, it is recognised that within this entity, a variety of morphological patterns can be found that may represent the evolution of the tumour.
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      The list of such examples is large and applies to every organ system in the body.
      In the kidney, many of the recognised forms of renal neoplasia may show considerable variation in morphology. Angiomyolipoma, a common benign tumour, can show varying amounts of its constituent tissues—to the extent that histologically different tissues may predominate, providing a marked range of morphologies.
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      Despite this, no attempt has been made to subclassify these tumours, which is entirely appropriate, as this would be clinically irrelevant. In this broad group of tumours the potentially malignant epitheloid angiomyolipoma is classified separately, which is justified on the basis of its differing morphology and clinical behaviour. Clear cell renal cell carcinoma, with clear or eosinophilic cells and typical vascular pattern of a regular network of small, thin-walled blood vessels can also display a variety of architectural patterns. Furthermore, while cytokeratin 7 (CK7) staining is usually negative in these tumours, intense and diffuse CK7 staining has been demonstrated in low grade and macrocytic patterns of clear cell renal cell carcinoma.
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      Despite architectural and immunohistochemical staining variations, these tumours are all classified as clear cell renal cell carcinoma and are graded, staged and treated accordingly.
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      The value of this is apparent, as a number of newly described categories had been previously labelled ‘unclassified’. However, their designation as a specific tumour type was valid as they were found to be distinctive both clinically and morphologically.
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      Benign eosinophilic renal tumours

      Early reports describing oncocytoma of the kidney noted that the tumour was characterised by uniform cells with eosinophilic cytoplasm due to the abundance of mitochondria.
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      Proximal tubular adenomas of kidney with so-called oncocytic features. A clinicopathologic study of 13 cases of a rarely reported neoplasm.
      In these tumours, tightly packed nests, cords, tubules and cysts are composed of cells with voluminous, granular, brightly eosinophilic cytoplasm and round uniform nuclei, sometimes with prominent nucleoli. In some areas, hyalinised vessels and oedematous vascular stroma may be seen. Several follow-up studies have confirmed that these tumours are clinically benign.
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      Renal oncocytoma.
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      Renal oncocytoma: a clinicopathological analysis of 45 consecutive cases.
      Ten years following the initial description of oncocytoma, Thoenes et al.
      • Thoenes W.
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      Renal cell carcinoma-a classification based on cytomorphological criteria.
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      Chromophobe renal cell carcinoma and its variants - a report on 32 cases.
      described chromophobe renal cell carcinoma (ChRCC), which included an eosinophilic variant with the same basic architecture as the classic variant. These tumours have polygonal cells with cell membrane thickening and finely granular cytoplasm, and a compact or solid growth pattern, with a delicate hyalinised stroma containing blood vessels. Tubular and cribriform patterns, laminar formation and microcystic spaces are also described. In the eosinophilic variant the cells are smaller and the cytoplasm more densely eosinophilic than that of the classic variant of the tumour, while paler cells, with reticular cytoplasm, are also regularly seen in these tumours. Nuclei are wrinkled, and are variable in size, being small, medium-sized or large, while the chromatin is dense. Perinuclear clearing is evident and this correlates with the electron microscopic identification of inner microvesicles.
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      Renal cell carcinoma-a classification based on cytomorphological criteria.
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      • Werner S.
      Chromophobe renal cell carcinoma and its variants - a report on 32 cases.
      CK7 immunostaining in the classic and eosinophilic variants in this study varied from the more common uniform homogeneous membranous staining, to the staining of a few individual cells.
      • Thoenes W.
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      • Moll R.
      • Baum H.P.
      • Werner S.
      Chromophobe renal cell carcinoma and its variants - a report on 32 cases.
      While most oncocytomas show negative or very patchy CK7 immunoexpression, it is our experience that rarely there may be diffuse staining. In comparison to oncocytoma, ChRCC displays a differing molecular profile, with multiple complete chromosome losses.
      • Kovacs G.
      Molecular differential pathology of renal cell tumours.
      Although ChRCC has metastatic potential, the prognosis is more favourable than that for clear cell renal cell carcinoma,
      • Thoenes W.
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      Chromophobe renal cell carcinoma and its variants - a report on 32 cases.
      ,
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      Classic chromophobe renal cell carcinoma incur a larger number of chromosomal losses than seen in the eosinophilic subtype.
      with no survival differences between the eosinophilic and classic variants.
      • Ohashi R.
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      • et al.
      Classic chromophobe renal cell carcinoma incur a larger number of chromosomal losses than seen in the eosinophilic subtype.
      Despite the absence of prognostic differences, classic ChRCC has been shown to have a greater number of chromosomal losses than that seen in the eosinophilic subtype.
      • Ohashi R.
      • Schraml P.
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      Classic chromophobe renal cell carcinoma incur a larger number of chromosomal losses than seen in the eosinophilic subtype.
      There are a variety of neoplasms that resemble, but are not diagnostic of oncocytoma or ChRCC. Hybrid oncocytic chromophobe tumour (HOCT) is described as an entity with features overlapping with oncocytoma and ChRCC, but appear to be molecularly distinct from these tumours.
      • Srigley J.R.
      • Delahunt B.
      • Eble J.N.
      • et al.
      The International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia.
      ,
      • Ruiz-Cordero R.
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      • Li L.
      • et al.
      Hybrid oncocytic/chromophobe renal tumors are molecularly distinct from oncocytoma and chromophobe renal cell carcinoma.
      These tumours may or may not be associated with familial syndromes and can display a variety of morphological features including a solid alveolar pattern of oncocytic cells having uniform nuclei without wrinkling, but with perinuclear clearing.
      • Hes O.
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      Renal hybrid oncocytic/chromophobe tumors - a review.
      • Waldert M.
      • Klatte T.
      • Haitel A.
      • et al.
      Hybrid renal cell carcinomas containing histopathologic features of chromophobe renal cell carcinomas and oncocytomas have excellent oncologic outcomes.
      • Petersson F.
      • Gatalica Z.
      • Grossmann P.
      • et al.
      Sporadic hybrid oncocytic/chromophobe tumor of the kidney: a clinicopathologic, histomorphologic, immunohistochemical, ultrastructural, and molecular cytogenetic study of 14 cases.
      Other patterns included in HOCT include; an admixture of oncocytoma and ChRCC, scattered chromophobe cells in a background of oncocytoma, or large eosinophilic cells with intracytoplasmic vacuoles.
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      • Kuroda N.
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      • Michal M.
      Renal hybrid oncocytic/chromophobe tumors - a review.
      • Waldert M.
      • Klatte T.
      • Haitel A.
      • et al.
      Hybrid renal cell carcinomas containing histopathologic features of chromophobe renal cell carcinomas and oncocytomas have excellent oncologic outcomes.
      • Petersson F.
      • Gatalica Z.
      • Grossmann P.
      • et al.
      Sporadic hybrid oncocytic/chromophobe tumor of the kidney: a clinicopathologic, histomorphologic, immunohistochemical, ultrastructural, and molecular cytogenetic study of 14 cases.
      The extent of CK7 staining demonstrated in these tumours is variable. In one study, oncocytomas with >10% CK7 positive cells was reclassified as HOCT.
      • Waldert M.
      • Klatte T.
      • Haitel A.
      • et al.
      Hybrid renal cell carcinomas containing histopathologic features of chromophobe renal cell carcinomas and oncocytomas have excellent oncologic outcomes.
      In another study of HOCT, nine of 14 cases displayed diffuse strong positivity for CK7 with two other cases showing moderate positivity. In these cases, CD117 was negative or only focally weakly positive in 10 of 14 cases.
      • Petersson F.
      • Gatalica Z.
      • Grossmann P.
      • et al.
      Sporadic hybrid oncocytic/chromophobe tumor of the kidney: a clinicopathologic, histomorphologic, immunohistochemical, ultrastructural, and molecular cytogenetic study of 14 cases.
      In contrast to ChRCC which has a low risk of metastasis,
      • Thoenes W.
      • Störkel S.
      • Rumpelt H.J.
      • Jacobi G.H.
      Renal cell carcinoma-a classification based on cytomorphological criteria.
      HOCT are apparently indolent tumours with no reported metastases.
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      • Eble J.N.
      • et al.
      The International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia.
      ,
      • Hes O.
      • Petersson F.
      • Kuroda N.
      • Hora M.
      • Michal M.
      Renal hybrid oncocytic/chromophobe tumors - a review.
      ,
      • Waldert M.
      • Klatte T.
      • Haitel A.
      • et al.
      Hybrid renal cell carcinomas containing histopathologic features of chromophobe renal cell carcinomas and oncocytomas have excellent oncologic outcomes.
      ,
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      • Galmiche L.
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      Hybrid tumour 'oncocytoma-chromophobe renal cell carcinoma' of the kidney: a report of seven sporadic cases.
      So-called low-grade oncocytic tumour (LOT) emerged in 2018 when this entity was first described based on a series of 28 oncocytic tumours.
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      New and emerging renal entities: a perspective post-WHO 2016 classification.
      ,
      • Trpkov K.
      • Williamson S.R.
      • Gao Y.
      • et al.
      Low-grade oncocytic tumour of kidney (CD117-negative, cytokeratin 7-positive): a distinct entity?.
      These tumours strongly resembled oncocytoma morphologically, but had a predominantly solid architecture, focal perinucleolar clearing and were shown to have diffuse CK7 positivity and CD117 negativity.
      Unfortunately, crucial information relating to what proportion of each tumour was blocked and submitted for histological examination and how much tissue was subjected to immunostaining was not provided. It was also stated that negative staining for CD117 in the presence of diffuse CK7 staining was diagnostic of this entity. This is surprising as HOCT can have similar staining as well as similar morphology on routine staining.
      • Petersson F.
      • Gatalica Z.
      • Grossmann P.
      • et al.
      Sporadic hybrid oncocytic/chromophobe tumor of the kidney: a clinicopathologic, histomorphologic, immunohistochemical, ultrastructural, and molecular cytogenetic study of 14 cases.
      It would seem that in this original series of LOT, cases of HOCT had not been excluded with certainty. Interestingly, the original publication on LOT
      • Trpkov K.
      • Hes O.
      New and emerging renal entities: a perspective post-WHO 2016 classification.
      referred to an earlier study reported by Kuroda et al.,
      • Kuroda N.
      • Tanaka A.
      • Yamaguchi T.
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      Chromophobe renal cell carcinoma, oncocytic variant: a proposal of a new variant giving a critical diagnostic pitfall in diagnosing renal oncocytic tumors.
      and it was claimed that Kuroda's series of tumours were similar to LOT, with a similar immunoprofile despite all five cases having multiple chromosomal losses and being designated ChRCC.
      • Trpkov K.
      • Hes O.
      New and emerging renal entities: a perspective post-WHO 2016 classification.
      ,
      • Kuroda N.
      • Tanaka A.
      • Yamaguchi T.
      • et al.
      Chromophobe renal cell carcinoma, oncocytic variant: a proposal of a new variant giving a critical diagnostic pitfall in diagnosing renal oncocytic tumors.
      All cases of LOT with available follow-up had no disease progression,
      • Trpkov K.
      • Williamson S.R.
      • Gao Y.
      • et al.
      Low-grade oncocytic tumour of kidney (CD117-negative, cytokeratin 7-positive): a distinct entity?.
      which is similar to the outcome with HOCT and oncocytoma.
      • Srigley J.R.
      • Delahunt B.
      • Eble J.N.
      • et al.
      The International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia.
      ,
      • Hes O.
      • Petersson F.
      • Kuroda N.
      • Hora M.
      • Michal M.
      Renal hybrid oncocytic/chromophobe tumors - a review.
      ,
      • Waldert M.
      • Klatte T.
      • Haitel A.
      • et al.
      Hybrid renal cell carcinomas containing histopathologic features of chromophobe renal cell carcinomas and oncocytomas have excellent oncologic outcomes.
      Interestingly, a subsequent publication of an ‘update of renal neoplasia’ by the Untited States-based Genitourinary Pathology Society (GUPS) suggested the term ‘oncocytic renal neoplasm of low malignant potential, not further classified’ for tumours with ‘borderline’ features between oncocytoma and ChRCC.
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      • Hes O.
      • Williamson S.R.
      • et al.
      New developments in the existing WHO entities and evolving molecular concepts: the Genitourinary Pathology Society (GUPS) update on renal neoplasia.
      In particular, they proposed the use of this term for sporadic cases of HOCT. This has been adopted in the latest World Health Organization (WHO) renal tumour classification, with the slightly modified terminology ‘oncocytic renal neoplasm of low malignant potential, NOS (not further specified)’, despite a lack of international consensus.
      WHO Classification of Tumours Editorial Board
      World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs.
      Furthermore, no reason is given for this suggested substitution of diagnostic terminology. The term ‘oncocytic renal neoplasm of low malignant potential, not further classified’ is unfortunate as the tumours included appear benign and the phrase has been added either as a medicolegal safety net or to highlight the diagnostic confusion of the authors. How ‘oncocytic renal neoplasm of low malignant potential, not further classified’ differs from the entity labelled LOT is not discussed apart from stating that LOT ‘typically’ lacks ‘significant’ nuclear irregularities and is negative for CD117. This is somewhat surprising as these features have been previously described in HOCT.
      • Ohashi R.
      • Schraml P.
      • Angori S.
      • et al.
      Classic chromophobe renal cell carcinoma incur a larger number of chromosomal losses than seen in the eosinophilic subtype.
      • Ruiz-Cordero R.
      • Rao P.
      • Li L.
      • et al.
      Hybrid oncocytic/chromophobe renal tumors are molecularly distinct from oncocytoma and chromophobe renal cell carcinoma.
      • Hes O.
      • Petersson F.
      • Kuroda N.
      • Hora M.
      • Michal M.
      Renal hybrid oncocytic/chromophobe tumors - a review.
      Interestingly, the authors do admit that there is significant morphological and immunohistochemical overlap of the tumours in the oncocytoma-eosinophilic ChRCC spectrum.
      • Trpkov K.
      • Hes O.
      • Williamson S.R.
      • et al.
      New developments in the existing WHO entities and evolving molecular concepts: the Genitourinary Pathology Society (GUPS) update on renal neoplasia.
      While the initial reports of LOT described single tumours in a non-syndromic setting,
      • Trpkov K.
      • Hes O.
      New and emerging renal entities: a perspective post-WHO 2016 classification.
      ,
      • Trpkov K.
      • Williamson S.R.
      • Gao Y.
      • et al.
      Low-grade oncocytic tumour of kidney (CD117-negative, cytokeratin 7-positive): a distinct entity?.
      subsequent reports have shown differing results. A study by Lerma et al.
      • Lerma L.A.
      • Schade G.R.
      • Tretiakova M.S.
      Co-existence of ESC-RCC, EVT and LOT as synchronous and metachronous tumours in six patients with multifocal neoplasia but without clinical features of tuberous sclerosis complex.
      described 14 such tumours in 10 nephrectomies occurring in association with other oncocytic tumours such as eosinophilic vacuolated tumour (EVT) and eosinophilic solid and cystic renal cell carcinoma and it was claimed that these tumours were related. Some of these cases had evidence of tuberous sclerosis (TSC) complex and some had end-stage renal disease.
      • Lerma L.A.
      • Schade G.R.
      • Tretiakova M.S.
      Co-existence of ESC-RCC, EVT and LOT as synchronous and metachronous tumours in six patients with multifocal neoplasia but without clinical features of tuberous sclerosis complex.
      Others have performed immunohistochemistry on tumours resembling oncocytoma and 79 other cases displaying CK7+/CD117 – immunophenotype, interpreted as consistent with LOT, have been reported.
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      Characterization of a distinct low grade oncocytic renal tumor (CD117-negative and cytokeratin 7-positive) based on a tertiary oncology center experience: the new evidence from China.
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      • et al.
      Low-grade oncocytic tumor of kidney (CK7-positive, CD117-negative): incidence in a single institutional experience with clinicopathological and molecular characteristics.
      • Akgul M.
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      • Cheng L.
      • Idrees M.T.
      Low-grade oncocytic tumour expands the spectrum of renal oncocytic tumours and deserves separate classification: a review of 23 cases from a single tertiary institute.
      • Kapur P.
      • Gao M.
      • Zhong H.
      Germline and sporadic mTOR pathway mutations in low-grade oncocytic tumor of the kidney.
      • Sharma D.
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      • Desai S.
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      Low-grade oncocytic tumor: report of two cases of an emerging entity in the spectrum of oncocytic renal neoplasms.
      • Morini A.
      • Drossart T.
      • Timsit M.O.
      • et al.
      Low-grade oncocytic renal tumor (LOT): mutations in mTOR pathway genes and low expression of FOXI1.
      These included eight cases from China
      • Guo Q.
      • Liu N.
      • Wang F.
      • et al.
      Characterization of a distinct low grade oncocytic renal tumor (CD117-negative and cytokeratin 7-positive) based on a tertiary oncology center experience: the new evidence from China.
      (0.17% of 4456 consecutive renal tumours), 29 cases from the Mayo Clinic
      • Kravtsov O.
      • Gupta S.
      • Cheville J.C.
      • et al.
      Low-grade oncocytic tumor of kidney (CK7-positive, CD117-negative): incidence in a single institutional experience with clinicopathological and molecular characteristics.
      (from a series of renal tumours between 1970 and 2012), 23 cases from the Indiana University
      • Akgul M.
      • Al-Obaidy K.I.
      • Cheng L.
      • Idrees M.T.
      Low-grade oncocytic tumour expands the spectrum of renal oncocytic tumours and deserves separate classification: a review of 23 cases from a single tertiary institute.
      (from a series of renal tumours between 2005 and 2020), seven cases from the University of Texas Southwestern Medical Center
      • Kapur P.
      • Gao M.
      • Zhong H.
      Germline and sporadic mTOR pathway mutations in low-grade oncocytic tumor of the kidney.
      (from a series of renal tumours between 2005 and 2016), two cases from India,
      • Sharma D.
      • Pai T.
      • Prakash G.
      • Desai S.
      • Menon S.
      Low-grade oncocytic tumor: report of two cases of an emerging entity in the spectrum of oncocytic renal neoplasms.
      and 10 cases from France.
      • Morini A.
      • Drossart T.
      • Timsit M.O.
      • et al.
      Low-grade oncocytic renal tumor (LOT): mutations in mTOR pathway genes and low expression of FOXI1.
      Despite actively querying large renal tumour databases of many years standing, the number of cases of LOT identified has been only a very small proportion of these large series of renal tumours. Some of these studies demonstrated alterations in the TSC/mammalian target of rapamycin (mTOR) pathway to be a feature of LOT,
      • Kapur P.
      • Gao M.
      • Zhong H.
      Germline and sporadic mTOR pathway mutations in low-grade oncocytic tumor of the kidney.
      ,
      • Morini A.
      • Drossart T.
      • Timsit M.O.
      • et al.
      Low-grade oncocytic renal tumor (LOT): mutations in mTOR pathway genes and low expression of FOXI1.
      and found that in a clinical setting these tumours could occur sporadically, or be associated with TSC or end-stage renal disease.
      • Kapur P.
      • Gao M.
      • Zhong H.
      Germline and sporadic mTOR pathway mutations in low-grade oncocytic tumor of the kidney.
      Recently Zhang et al. reported seven cases they identified as LOT from their files of 2153 renal tumours.
      • Zhang H.-Z.
      • Xia Q.-Y.
      • Wang S.-Y.
      • Shi M.-J.
      • Wang S.-Y.
      Low grade oncocytic tumour of kidney harbouring TSC/MTOR mutation: clinicopathologic, immunohistochemical and molecular characteristics support a distinct entity.
      Four of the tumours showed mutations in TSC1 and TSC2, while one had mutations in mTOR and TSC2. Somewhat surprisingly two of the tumours were negative for these mutations on next generation sequencing. All cases were CK7 positive and five were negative for CD117, while two (including one showing TSC1 and TSC2 mutations) showed only weak and non-specific CD117 staining. It is apparent from this study and earlier ones, that there are a variety of chromosomal abnormalities associated with tumours classified as LOT. Zheng et al. found gains of 6p, 18p, 22q, 7p and 7q; however, these results differed from previous studies and it was concluded that LOT lacked consistent chromosomal losses and gains.
      • Zhang H.-Z.
      • Xia Q.-Y.
      • Wang S.-Y.
      • Shi M.-J.
      • Wang S.-Y.
      Low grade oncocytic tumour of kidney harbouring TSC/MTOR mutation: clinicopathologic, immunohistochemical and molecular characteristics support a distinct entity.
      It is important to note that TSC/mTOR mutations have also been demonstrated in many renal tumours including angiomyolipomas
      • Budde K.
      • Gaedeke J.
      Tuberous sclerosis complex-associated angiomyolipomas: focus on mTOR inhibition.
      and other eosinophilic tumours such as eosinophilic solid and cystic renal cell carcinoma,
      • Mehra R.
      • Vats P.
      • Cao X.
      • et al.
      Somatic bi-allelic loss of TSC genes in eosinophilic solid and cystic renal cell carcinoma.
      ChRCC
      • Roldan-Romero J.M.
      • Santos M.
      • Lanillos J.
      • et al.
      Molecular characterisation of chromophobe renal cell carcinoma reveals mTOR pathway alterations in patients with poor outcome.
      and epithelioid angiomyolipoma.
      • Caliò A.
      • Brunelli M.
      • Segala D.
      • et al.
      Angiomyolipoma of the kidney: from simple hamartoma to complex tumour.
      Tjota et al. reviewed 18 eosinophilic renal tumours with unusual morphologies and found TSC/mTOR mutations across all morphological patterns.
      • Tjota M.
      • Chen H.
      • Parilla M.
      • Wanjari P.
      • Segal J.
      • Antic T.
      Eosinophilic renal cell tumors with a TSC and MTOR gene mutations are morphologically and immunohistochemically heterogenous: clinicopathologic and molecular study.
      None of these cases had been diagnosed as LOT. Notwithstanding, this publication is cited in the 2022 WHO classification as evidence of the existence of LOT as a diagnostic entity.
      WHO Classification of Tumours Editorial Board
      World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs.
      The reason why archives from so many institutions were queried for more cases of LOT, despite their uniformly indolent behaviour and lack of unique morphology, remains unclear. As noted above, there are numerous other more morphologically diverse tumours which remain within a single diagnostic category because of a pragmatic approach to diagnosis and prognostication, backed by evidence, while the identification of LOT as a diagnostic entity has no clinical utility.
      High grade oncocytic tumour (HOT) is another ‘entity’ that has recently emerged from the oncocytic tumour category.
      • Trpkov K.
      • Williamson S.R.
      • Gao Y.
      • et al.
      Low-grade oncocytic tumour of kidney (CD117-negative, cytokeratin 7-positive): a distinct entity?.
      ,
      • He H.
      • Trpkov K.
      • Martinek P.
      • et al.
      "High-grade oncocytic renal tumor": morphologic, immunohistochemical, and molecular genetic study of 14 cases.
      After searching multiple institutional archives, 14 cases were thought to have similar morphology and to be distinct from other oncocytic tumours.
      • He H.
      • Trpkov K.
      • Martinek P.
      • et al.
      "High-grade oncocytic renal tumor": morphologic, immunohistochemical, and molecular genetic study of 14 cases.
      While these cases had no stated association with TSC, a similar case was subsequently reported from a patient with TSC.
      • Trpkov K.
      • Bonert M.
      • Gao Y.
      • et al.
      High-grade oncocytic tumour (HOT) of kidney in a patient with tuberous sclerosis complex.
      Tumours were described as having nested to solid growth with focal tubulocystic architecture, being composed of cells with voluminous cytoplasm, which was either eosinophilic (oncocytic) or clear. Eosinophilic cells containing large cytoplasmic vacuoles were found in all 14 cases, but were prominent in six of the 14 cases. Cells lacked irregular nuclei and perinuclear halos and contained prominent nucleoli. Calcification was not a stated characteristic in these tumours. All cases were in staging category pT1 and there was no progression in 10 cases with follow-up of 1–112 months.
      • He H.
      • Trpkov K.
      • Martinek P.
      • et al.
      "High-grade oncocytic renal tumor": morphologic, immunohistochemical, and molecular genetic study of 14 cases.
      Interestingly, the defining characteristics of HOT have been described in other oncocytic tumours. Intracytoplasmic vacuoles have been reported in HOCT.
      • Hes O.
      • Petersson F.
      • Kuroda N.
      • Hora M.
      • Michal M.
      Renal hybrid oncocytic/chromophobe tumors - a review.
      • Waldert M.
      • Klatte T.
      • Haitel A.
      • et al.
      Hybrid renal cell carcinomas containing histopathologic features of chromophobe renal cell carcinomas and oncocytomas have excellent oncologic outcomes.
      • Petersson F.
      • Gatalica Z.
      • Grossmann P.
      • et al.
      Sporadic hybrid oncocytic/chromophobe tumor of the kidney: a clinicopathologic, histomorphologic, immunohistochemical, ultrastructural, and molecular cytogenetic study of 14 cases.
      Large nucleoli [WHO/International Society of Urological Pathology (ISUP) grade 3 equivalent] have also been described in oncocytoma,
      • Amin M.B.
      • Crotty T.B.
      • Tickoo S.K.
      • Farrow G.M.
      Renal oncocytoma: a reappraisal of morphologic features with clinicopathologic findings in 80 cases.
      and similar to oncocytoma, some cases were positive for CD117 while CK7 was negative or only focally (<50%) positive.
      • He H.
      • Trpkov K.
      • Martinek P.
      • et al.
      "High-grade oncocytic renal tumor": morphologic, immunohistochemical, and molecular genetic study of 14 cases.
      Large nucleoli are not a unique diagnostic characteristic for oncocytic renal tumours and also occur in some low-grade neoplasms of the kidney such as tubulocystic carcinoma.
      • Delahunt B.
      • Srigley J.R.
      • Montironi R.
      • Egevad L.
      Advances in renal neoplasia: recommendations from the 2012 International Society of Urological Pathology Consensus Conference.
      As such, it would seem inappropriate to utilise nuclear size as a major criterion for a novel diagnostic entity. The descriptor HOT implies an aggressive clinical course which would not seem to be the case, while other high grade features such as granular tumour necrosis,
      • Samaratunga H.
      • Delahunt B.
      • Srigley J.R.
      • et al.
      Granular necrosis: distinctive form of cell death in malignant tumours.
      frequent mitoses, vascular invasion, high stage and metastasis have not been reported.
      A recent study by Chen et al. identified seven ‘morphologically distinct oncocytic tumours’ from non-syndromic patients. These tumours had a predominantly nested architecture, eosinophilic and vacuolated cytoplasm, round nuclei and prominent nucleoli.
      • Chen Y.B.
      • Mirsadraei L.
      • Jayakumaran G.
      • et al.
      Somatic mutations of TSC2 or MTOR characterize a morphologically distinct subset of sporadic renal cell carcinoma with eosinophilic and vacuolated cytoplasm.
      In this group, calcification was frequently found. None of the six tumours tested were positive for CK7 and four of seven cases displayed weak CD117 positivity. Next generation sequencing identified somatic inactivating mutations of TSC2 (3/5 cases) or activating mutations in mTOR (2/5 cases). Copy number analysis revealed loss of chromosome 1 in both cases with mTOR mutations. These tumours were originally labelled renal cell carcinoma with eosinophilic and vacuolated cytoplasm. In a subsequent report, and despite the presence of calcification that had not been previously mentioned as a defining feature of HOT, these seven cases were re-designated as HOT.
      • Trpkov K.
      • Bonert M.
      • Gao Y.
      • et al.
      High-grade oncocytic tumour (HOT) of kidney in a patient with tuberous sclerosis complex.
      HOT has now been re-named EVT.
      • Trpkov K.
      • Williamson S.R.
      • Gill A.
      • et al.
      Novel, emerging and provisional renal entities: the Genitourinary Pathology Society (GUPS) update on renal neoplasia.
      EVT has been designated an ‘emerging’ renal tumour in the 2022 WHO Renal Tumour Classification
      WHO Classification of Tumours Editorial Board
      World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs.
      where, somewhat surprisingly, the case series of Chen et al.
      • Chen Y.B.
      • Mirsadraei L.
      • Jayakumaran G.
      • et al.
      Somatic mutations of TSC2 or MTOR characterize a morphologically distinct subset of sporadic renal cell carcinoma with eosinophilic and vacuolated cytoplasm.
      is cited in relation to the diagnosis of EVT. Interestingly, a study by Tjota et al.
      • Tjota M.
      • Chen H.
      • Parilla M.
      • Wanjari P.
      • Segal J.
      • Antic T.
      Eosinophilic renal cell tumors with a TSC and MTOR gene mutations are morphologically and immunohistochemically heterogenous: clinicopathologic and molecular study.
      is also cited in the reference list of HOT in the new WHO classification,
      WHO Classification of Tumours Editorial Board
      World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs.
      even though none of the cases in that study had morphological features considered to be typical of this entity.
      More recently a study has evaluated 19 renal tumours thought to have morphological and immunohistochemical features consistent with EVT, of which the details of three had been published previously.
      • He H.
      • Trpkov K.
      • Martinek P.
      • et al.
      "High-grade oncocytic renal tumor": morphologic, immunohistochemical, and molecular genetic study of 14 cases.
      The other cases in the series were obtained from more than 15 institutions internationally.
      • Farcaş M.
      • Gatalica Z.
      • Trpkov K.
      • et al.
      Eosinophilic vacuolated tumor (EVT) of kidney demonstrates sporadic TSC/MTOR mutations: next-generation sequencing multi-institutional study of 19 cases.
      Follow-up, ranging from 12 to 198 months, was available for 18 patients and with no reported recurrence or progression. None of the patients had evidence of TSC and all 19 cases showed mutations of the mTOR pathway genes. Copy number variations were not found in any of the 17 analysed cases. The somewhat surprising conclusion was that the finding of mutations of mTOR pathway genes was further evidence that EVT was a novel entity.

      Genetic findings

      Much emphasis has been placed recently on the role of mTOR pathway mutations in the pathogenesis of these tumours. Unfortunately, these mutations are not unique to LOT and EVT as is further illustrated in a recent case report of a metastasising renal cell carcinoma with mTOR mutations.
      • Tjota M.Y.
      • Segal J.
      • Stadler W.M.
      Antic T. Eosinophilic renal cell carcinoma with isolated MTOR mutation metastatic to the liver: a novel case.
      Furthermore the mutations in the mTOR pathway are not consistent and may be any combination of TSC1, TSC2 and mTOR. Genomic characterisation of cancer is evolving as a useful clinical tool in personalised cancer treatments based on the behaviour and ontology of the tumour. Frequently found variants or variants associated with specific cancer morphology and behaviour are likely to be more functionally relevant. This can be of clinical utility if mutational status is indicative of response to treatment. A key challenge of precision medicine is meaningful and accurate interpretation of genomic data. A large number of somatic gene alterations occur in any given individual tumour in an individual patient. Not all variants in a given gene will have the same phenotypic effect. There are common cancer genes, which will be found to be mutated in multiple cancers and their subtypes, and are a consequence of cancer progression rather than a molecular profile unique to the cancer subtype. Zhang et al. carried out a comprehensive study in thousands of samples and looked at the P13K/AKT/mTOR pathway in 32 major types of human cancers.
      • Zhang Y.
      • Kwok-Shing Ng P.
      • Kucherlapati M.
      • et al.
      A pan-cancer proteogenomic atlas of PI3K/AKT/mTOR pathway alterations.
      A considerable fraction (4468 of 7099) of the tumour cases examined had at least one non-silent somatic mutation or copy alteration involving the PI3K/AKT/mTOR pathway. Large sample sizes are key in order to detect robust molecular profiles that are genuinely meaningful clinically and scientifically; the study above demonstrates many key cancer gene mutations will be found in many cancers that are not subtype specific. Often small powered studies focus on genes of interest rather than reporting entire mutational findings. An example of this is the study by Kapur et al.
      • Kapur P.
      • Gao M.
      • Zhong H.
      Germline and sporadic mTOR pathway mutations in low-grade oncocytic tumor of the kidney.
      that reported on mTOR pathway mutations in 22 tumours from seven patients classified as having low-grade oncocytic tumour. The study employed whole exome sequencing and would typically generate mutational data from more than 500 genes, as also seen in the study by Durinck et al.
      • Durinck S.
      • Stawiski E.W.
      • Pavía-Jiménez A.
      • et al.
      Spectrum of diverse genomic alterations define non-clear cell renal carcinoma subtypes.
      Despite this, the authors only report on the genes that were of interest to the research question, focusing on a subset of molecular data in a small cohort to support a pathway-driven hypothesis for subtype classification. Such an approach is unlikely to result in clinically or scientifically meaningful classifications due to significant biological and technical noise in such a small sample set and common mutational pathways in many different cancers.
      The reported cases of LOT and HOT lack multiple complete chromosomal losses and gains,
      • Trpkov K.
      • Hes O.
      New and emerging renal entities: a perspective post-WHO 2016 classification.
      ,
      • He H.
      • Trpkov K.
      • Martinek P.
      • et al.
      "High-grade oncocytic renal tumor": morphologic, immunohistochemical, and molecular genetic study of 14 cases.
      similar to HOCT
      • Srigley J.R.
      • Delahunt B.
      • Eble J.N.
      • et al.
      The International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia.
      ,
      • Ruiz-Cordero R.
      • Rao P.
      • Li L.
      • et al.
      Hybrid oncocytic/chromophobe renal tumors are molecularly distinct from oncocytoma and chromophobe renal cell carcinoma.
      and oncocytoma,
      • Zhang Y.
      • Kwok-Shing Ng P.
      • Kucherlapati M.
      • et al.
      A pan-cancer proteogenomic atlas of PI3K/AKT/mTOR pathway alterations.
      and are different to that reported for ChRCC.
      • Kovacs G.
      Molecular differential pathology of renal cell tumours.
      ,
      • Ohashi R.
      • Schraml P.
      • Angori S.
      • et al.
      Classic chromophobe renal cell carcinoma incur a larger number of chromosomal losses than seen in the eosinophilic subtype.
      LOT and HOT display morphological and immunohistochemical overlap with HOCT and oncocytoma, and like oncocytoma are biologically indolent tumours.
      • Trpkov K.
      • Williamson S.R.
      • Gao Y.
      • et al.
      Low-grade oncocytic tumour of kidney (CD117-negative, cytokeratin 7-positive): a distinct entity?.
      ,
      • He H.
      • Trpkov K.
      • Martinek P.
      • et al.
      "High-grade oncocytic renal tumor": morphologic, immunohistochemical, and molecular genetic study of 14 cases.
      Using comparative genomics hybridisation, nine (of 28) cases of LOT showed deletions at 19p13.3 in seven cases, 19q13.11 in four cases and 1p13.33 in five cases.
      • Trpkov K.
      • Williamson S.R.
      • Gao Y.
      • et al.
      Low-grade oncocytic tumour of kidney (CD117-negative, cytokeratin 7-positive): a distinct entity?.
      Analysis of nine cases of HOT have also shown deletions on chromosome 19 in four cases (3 with losses on 19p and 1 with losses on p and q) and on chromosome 1 in four of nine cases.
      • He H.
      • Trpkov K.
      • Martinek P.
      • et al.
      "High-grade oncocytic renal tumor": morphologic, immunohistochemical, and molecular genetic study of 14 cases.
      Three of these nine cases did not show any abnormality. Molecular karyotyping analysis was available for only three cases in this study, all of which showed a diploid pattern. All three cases examined displayed loss of heterozygosity (LOH) on 16p11.2-11.1 with two of three cases showing LOH at 7q31.31. Copy number losses were found at 7q11.21 (3/3), Xp11.21 (3/3), Xp11.22-11.21 (3/3) and Xq24-25 (2/3). Copy number gains were found at 13q34 in two of three cases. As is the case for HOT, ploidy studies of LOT have shown the tumour to be diploid.
      • Trpkov K.
      • Williamson S.R.
      • Gao Y.
      • et al.
      Low-grade oncocytic tumour of kidney (CD117-negative, cytokeratin 7-positive): a distinct entity?.
      In oncocytomas, deletions in chromosome 1, 14, X or Y or random genetic changes have been described,
      • Yusenko M.V.
      • Kuiper R.P.
      • Boethe T.
      • et al.
      High-resolution DNA copy number and gene expression analyses distinguish chromophobe renal cell carcinomas and renal oncocytomas.
      • Presti J.C.
      • Moch H.
      • Reuter V.E.
      • Huynh D.
      • Waldman F.M.
      Comparative genomic hybridisation for genetic analysis of renal oncocytomas.
      • Liu Y.J.
      • Ussakli C.
      • Antic T.
      • et al.
      Sporadic oncocytic tumors with features intermediate between oncocytoma and chromophobe renal cell carcinoma: comprehensive clinicopathological and genomic profiling.
      while studies on HOCT have found copy number alterations primarily involving losses in chromosome 1 and X/Y.
      • Ruiz-Cordero R.
      • Rao P.
      • Li L.
      • et al.
      Hybrid oncocytic/chromophobe renal tumors are molecularly distinct from oncocytoma and chromophobe renal cell carcinoma.
      ,
      • Liu Y.J.
      • Ussakli C.
      • Antic T.
      • et al.
      Sporadic oncocytic tumors with features intermediate between oncocytoma and chromophobe renal cell carcinoma: comprehensive clinicopathological and genomic profiling.
      A recent review by Trpkov et al.
      • Trpkov K.
      • Williamson S.R.
      • Gill A.
      • et al.
      Novel, emerging and provisional renal entities: the Genitourinary Pathology Society (GUPS) update on renal neoplasia.
      suggests that low or null FOXI1 (a forkhead family transcription factor related to intercalated cells) mRNA expression in LOT contrasts with that seen in renal oncocytoma and ChRCC. They cite a study by Tong and Hu.
      • Tong K.
      • Hu Z.
      FOXI1 expression in chromophobe renal cell carcinoma and renal oncocytoma: a study of the Cancer Genome Atlas transcriptome-based outlier mining and immunohistochemistry.
      who found five ‘difficult to classify’ oncocytic tumours with negative or focal immunostaining for FOXI1, which they designated eosinophilic ChRCC-like renal tumour. This study also found negative or focal FOXI1 immunostaining in 20% (of 93) ChRCCs (with diffuse strong positivity in only about half the cases), 33% (of 18) oncocytomas and 0% (of 2) HOCT. Despite these findings, Trpkov et al.
      • Trpkov K.
      • Williamson S.R.
      • Gill A.
      • et al.
      Novel, emerging and provisional renal entities: the Genitourinary Pathology Society (GUPS) update on renal neoplasia.
      conclude that these five cases are representative of LOT. A further study examining biomarker characterisation, including FOXI1 expression in ChRCC and related oncocytic neoplasms,
      • Skala S.L.
      • Wang X.
      • Zhang Y.
      • et al.
      Next-generation RNA sequencing-based biomarker characterization of chromophobe renal cell carcinoma and related oncocytic neoplasms.
      reported two cases that differed from ChRCC and oncocytoma, being diploid with mTOR gene mutations. This series included three additional cases from the TGGA database which had been diagnosed as ChRCC or papillary renal cell carcinoma, but lacked FOXI1 gene expression and were reclassified as mixed renal cell carcinoma with mTOR kinase domain mutations. The authors conclude that these cases suggest multiple molecular aberrations may be associated with the same histological subtype. This study is also cited in the 2022 WHO Bluebook as evidence of the existence of LOT.
      WHO Classification of Tumours Editorial Board
      World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs.

      Conclusions

      It is apparent that even in the small numbers of reported cases, there is much overlap in molecular genetic abnormalities in oncocytic tumours including so-called LOT, HOT, EVT and HOCT, but as a group they are clearly distinct from ChRCC. This underscores the current confusion and disagreement amongst practising pathologists relating to the current classification of oncocytic tumours.
      • Williamson S.R.
      • Gadde R.
      • Trpkov K.
      • et al.
      Diagnostic criteria for oncocytic renal neoplasms: a survey of urologic pathologists.
      ,
      • Mohanty S.K.
      • Lobo A.
      • Parwani A.W.
      • et al.
      The current state of emerging renal oncocytic neoplasms: a survey of urologic pathologists: 2021 USCAP Abstract 594.
      In a recent survey of urological pathologists, there was great variability in the interpretation of the diagnostic importance of focal nuclear wrinkling, perinuclear clearing, binucleation and multinucleation.
      • Williamson S.R.
      • Gadde R.
      • Trpkov K.
      • et al.
      Diagnostic criteria for oncocytic renal neoplasms: a survey of urologic pathologists.
      Another survey of 60 urological pathologists found uncertainty in oncocytic tumour diagnosis amongst 50% of the participants and 73% were uncertain about the validity of a diagnosis of LOT.
      • Mohanty S.K.
      • Lobo A.
      • Parwani A.W.
      • et al.
      The current state of emerging renal oncocytic neoplasms: a survey of urologic pathologists: 2021 USCAP Abstract 594.
      Tumour classification can be further confounded if it is based on an immunohistochemical profile, as clonal evolution of the tumour and potential sampling issues may produce conflicting results. Such immunoconfusion may be avoided if immunohistochemical studies are not performed on cases where the morphology is diagnostic. If there is failure to diagnose a case of LOT or HOT because immunohistochemistry was not performed or due to poor sampling, there does not appear to be any loss to patients who would have a diagnosis of oncocytoma or HOCT or even an ‘oncocytic neoplasm’, as these are all benign tumours. A diagnosis of carcinoma is not justified with the morphological features described in LOT and HOT in the absence of features of ChRCC or known aggressive characteristics. Grading of oncocytoma-like tumours and ChRCC is not performed in routine practice
      • Delahunt B.
      • Eble J.N.
      • Egevad L.
      • Samaratunga H.
      Grading of renal cell carcinoma.
      which is yet another reason why LOT and HOT terminology is inappropriate.
      It is clear that the presence of a mutation within a neoplasm does not necessarily indicate that it is active in the genesis or evolution of the tumour. The existence of multiple tumour morphotypes and differing clinical behaviour, associated with a single mutation, would argue to the contrary. LOT and EVT appear to have no unique and reproducible morphological characteristics or prognostic differences from similar tumours already described. The problems associated with expanding the renal tumour classification to include novel entities, with small numbers of cases in each category and without any realistic possibility of clinical evaluation due to rarity, has been discussed recently.
      • Eble J.N.
      Contributions of genetics to the evolution of the diagnostic classification of renal cell neoplasia: a personal perspective.
      It is apparent that, at present, there is no convincing evidence to indicate that LOT and HOT/EVT are distinct tumours.
      The confusion relating to the classification of oncocytic tumours is best exemplified by the establishment of a category of tumours designated ‘Other Oncocytic Tumours of the Kidney’ in the 5th edition of the WHO Classification of Renal Tumours.
      WHO Classification of Tumours Editorial Board
      World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs.
      Rather than having diagnostic utility, this is a non-entity defined by a constellation of often contradictory macroscopic and microscopic features, while there is no evidence as to how these tumours will behave. This group included EVT and LOT which, as noted above, are poorly characterised and incompletely defined. This diagnostic category does nothing more than add confusion by attempting to sub-categorise tumours that were previously identified as HOCT and oncocytoma.
      Clearly there is a spectrum of renal oncocytic tumours which are, by definition, benign. It is incumbent on practising pathologists to be aware of this spectrum and report cases accordingly. To attempt to separate this tumour group into multiple, albeit rare, diagnostic subgroups promotes confusion and adds no practical clinical value.

      Conflicts of interest and sources of funding

      The authors state that there are no conflicts of interest or sources of finding to disclose.

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